Project Summary/Abstract Human neural cells manufactured using patient-derived induced pluripotent stem cells (iPSCs) hold great promise for modeling neurodevelopmental disorders, discovering new precision therapies, and screening for potential risks from environmental toxins. However, biomanufacturing of neural cells and tissues is severely limited by low efficiency, poor reproducibility, and extended timeframes. Recent scientific discoveries, coupled with the substantial need for iPSC-derived neural cells in pharma applications, frame a significant commercial opportunity. Stem Pharm will address this opportunity by commercializing synthetic hydrogel technologies for biomanufacturing of iPSC-derived neural cells. Specifically, we will develop synthetic hydrogel substrates for iPSC-derived neural cell expansion, differentiation and high throughput screening workflows. The goal of this Phase I project is to develop chemically defined and robust synthetic hydrogels for efficient differentiation of iPSC-derived NPCs into cortical neurons and subsequent maturation to post-mitotic, functionally mature neurons. Specific Aim 1 will use synthetic hydrogel screening technologies to identify formulations that promote efficient differentiation of NPCs into post-mitotic cortical neurons. Specific Aim 2 will use synthetic hydrogel screening technologies to identify formulations that promote viability, retention and accelerated maturation of post-mitotic cortical neurons towards functional maturity. Specific Aim 3 will use a well-characterized neurodevelopmental disease line of Rett Syndrome to demonstrate the applicability and advantages of the identified hydrogel formulations for culturing challenging human disease-derived cells. This work is significant, as there is a critical need for better tools to optimize yields and reduce variability in the differentiation of iPSCs to defined neural subpopulations, support their long-term culture, and reduce the time needed to reach functional maturity. Successful completion of the proposed milestones will result in more effective biomanufacturing of neural cells and cell-based assays for precision medicine. This work is innovative, as our synthetic hydrogel screening technologies will identify hydrogel formulations for optimal differentiation and maturation of neural populations. These unique formulations can be discovered using the proprietary hydrogel screening approach developed and used by Stem Pharm, but once identified they can be used broadly across standard pharmaceutical workflows. Subsequent Phase II activities will demonstrate the performance of the unique hydrogel formulations in high throughput screening for toxicity testing and drug discovery.